1. Field of Invention
This invention relates to cannabinoids, and particularly relates to agonists and antagonists of cannabinoid that interact with brain cannabinoid (CB1) receptor. The invention includes analogs of SR14176A, a CB1 antagonist that blocks the actions of cannabinoids both in vivo and in vitro, as well as the use of these analogs.
2. Description of Prior Art
Cannabinoids are compounds derived from the cannabis sativa plant which is commonly known as marijuana. The most active chemical compound of the naturally occurring cannabinoids is tetrahydrocannabinol (THC), particularly xcex949-THC (FIG. 1b).
Marijuana based medicines have been known for centuries and have been a mainstay of many folk, herbal remedies. Many beneficial pharmacological properties can be attributed to marijuana. Among them are analgesia, lowering blood and intra-ocular pressure, and anti-emetic activity in both mammals and man. Beneficial effects of marijuana as well as its negative effects have been well documented. The negative pharmacological effects associated with marijuana (and later shown to be associated with THC) include psychological distortions of perception, loss of short-term memory, loss of motor coordination, sedation, and euphoria. Long term use of marijuana is considered by many to lead to addiction.
Two distinct types of receptors that bind both the naturally occurring and synthetic cannabinoids have been discovered. They are designated as CB1, the receptor located in the central nervous system, and as CB2, the receptor found in peripheral tissues. It is generally agreed that much of the cannabinoid pharmacology is associated with its effects on the central nervous system, and that these effects are directly related to the action of the CB1 receptor.
Synthetic and natural compounds, which are agonists of the CB1 receptor, demonstrate the expected experimental and human pharmacology, while closely related compounds that bind poorly to CB1 do not (Mechoulam et al.1994). Compounds that bind to brain cannabinoid (CB1) receptors show a large degree of diversity in chemical structure. These compounds include classical tricyclic and bicyclic cannabinoids, aminoalkylindoles, indoles, pyrroles, and anandamides. Each of these compounds shares a similar profile of pharmacological activity in vivo with the prototypic tricyclic cannabinoid, xcex949-tetrahydrocannabinol (xcex949-THC), albeit they differ in potency and in efficacy in individual assays (Adams et al., 1995; Compton et al., 1992, 1993; Wiley et al., 1998). These in vivo cannabimimetic effects include hypoactivity, hypothermia, antinociception and catalepsy in mice (Martin et al., 1991; Smith et al., 1994), xcex949-THC-like discriminative stimulus effects in rats and monkeys (see Wiley, 1999 for review), and static ataxia in dogs (Lichtman et al., 1998).
After the elucidation of THC structure, several synthetic compounds were prepared and found to be effective for the treatment of pain in cancer patients, among these are: nabilone, naboctate and levonantradol. Although these drugs are useful, they have to a greater or lesser extent some of the negative pharmacological properties of THC, and, thus, their general use is limited.
Non-cannabinoid analogs have also been developed. For example, Pacheco et al., reveals WIN 55,212-2, an aminoalkylindole (Pacheco et al., 1991, and Compton et al., 1992). U.S. Pat. No. 5,747,542 (Cullinan et al.) discloses aryl-benzo[b]thiophene and benzo[b]furan compounds. European Patent EP0576357 (Barth et al.) reveals halo-aryl pyrazoles, including SR 141716A.
SR 141716A (FIG. 1a) has been shown to block the actions of cannabinoids in in vivo and in vitro models (Rinaldi-Carmona et al., 1994). SR 141716A selectively binds to cannabinoid CB1 receptors without producing cannabimimetic activity in vivo (Compton et al., 1996), suggesting that binding and activation of cannabinoid receptors are separable events. Consequently, structure-activity relationship (SAR) studies with analogs of this antagonist provide a unique opportunity to compare the structural requirements for binding and antagonist activity to those required for binding and agonist efficacy. To date, only a couple of studies have been published which systematically examined the SAR of cannabinoid CB1 antagonists (Lan et al., 1999; Thomas et al., 1998). While both of these studies reported CB1 binding values for SR 141716A analogs, neither involved measurement of in vivo activity of the compound alone and in combination with a cannabinoid agonist.
There is much debate over whether marijuana use should be legalized in certain cases, such as its use in cancer patients for ameliorating the nausea induced by chemotherapy or to lower intra-ocular pressure in glaucoma patients. The effects of marijuana are thought to be due to its actions at CB1 receptors. Therefore, the logical alternative to marijuana is a synthetic cannabinoid agonist. Considering the beneficial effects of cannabinoids, it would be highly desirable to have an effective CB1 receptor agonist that produces fewer adverse effects than THC. The discovery of cannabinoid receptors and their endogenous ligands, such as anandamide and 2-arachidonyl-glycerol, led to the realization that an endogenous cannabinoid system exists. Therefore, an overactive endogenous cannabinoid system would be expected to produce THC-like effects, such as appetite stimulation and disruption of cognitive and. memory processes. The development of cannabinoid antagonists therefore will have therapeutic potential in treating obesity, memory deficits in disease states and psychopathology such as schizophrenia.
This invention provides a compound of formula I: 
(I), wherein
R1 is a phenyl that is unsubstituted or substituted one or more times by a halogen, or a C1-7 alkyl;
R2 is
an ether of formula
xe2x80x94CH2xe2x80x94Oxe2x80x94(CH2)mxe2x80x94R5
where R5is a heterocyclic, a C4-7 cycloalkyl, or an aryl, and m is 1 or 2,
an amide of formula 
where R6 is a C1-8 alkyl, a C1-6 haloalkyl, or a piperidine,
a ketone of formula 
where R7 is a C1-6 alkyl, or
an alcohol of formula 
where R8 is C1-6 alkyl;
R3 is a methyl, a hydrogen, or a halogen; and
R4 is a C1-8 alkyl or a phenyl that is unsubstituted or substituted one or more times by a halogen, or a C1-7 alkyl;
provided R6 is other than a C1-3 alkyl, where R1 and R4 are independently a phenyl that is unsubstituted or substituted one or more times by a halogen, or a unbranched C1-3 alkyl;
further provided R3 is other than a methyl, where R6 is a piperidine.
More specifically, the present invention involves the synthesis of a series of analogs of SR 141716A and the development of analogs with high receptor binding affinity and potential agonist and antagonist effects.
The invention also provides treatments which comprise administering an effective amount of a compound of formula I and pharmaceutical formulations which include a novel compound of formula (I) as an active ingredient in combination with a pharmaceutically acceptable carrier, diluent, or excipient to antagonize one or more of the actions of endogenous cannabinoids at brain cannabinoid (CB1) receptors in mammals.